The primary-progressive (PP) form represents 10% -15% of the overall multiple sclerosis (MS) patient population, -45,000 in the US. Compared with the more prevalent (~80%) relapsing-remitting (RR) form of the disease, PP-MS is characterized by a discrepancy between the severity of clinical deterioration and the paucity of MRI indicators: Fewer lesions, lower lesion formation rate, and less contrast enhancement. The insensitivity of the radiological markers has precluded PP-MS patients from most randomized trials of new treatments, in which efficacy is evaluated by both clinical outcomes and MRI metrics (number of enhancing and new T2 lesions). Consequently, no treatments are currently offered, even though the prognosis for this phenotype is worse than for RR-MS. It has been suggested that the disparity between clinical and MR findings might be due to MRI-occult brain pathology. Therefore, our central premise is that such diffuse microscopic damage must play a key role in disease progression, leading us to formulate three hypotheses: [unreadable] [unreadable] Hypothesis 1 (HI): Ongoing axonal damage, reflected by whole-brain ./V-acetylaspartate (WBNAA) deficit, will be greater in PP-MS than in RR-MS and will correlate with poorer cognitive performance. Hypothesis 2 (H2): Choline (Cho) and creatine (Cr) levels will be lower in PP-MS than in RR-MS patients, reflecting less inflammation and oligodendrocyte apoptosis; finally, wyo-inositol (ml) levels will be higher due to increased gliosis; Hypothesis 3 (H3): perfusion-MRI metrics (cerebral blood flow and mean transit time) will be more impaired in PP-MS than in RR-MS patients, due to less intense but more prolonged inflammation. The perfusion metrics will be correlated with cerebrospinal fluid (CSF) and blood levels of tumor necrosis factor-a (TNF-a) which is related to ischemic injury and neurodegeneration. To test these hypotheses we propose three Specific Aims: Specific Aim 1: To compare the WBNAA, Cho, Cr and ml levels in PP-MS, age and sex matched RR-MS and healthy control subjects. Specific Aim 2: To compare the perfusion MRI metrics in the same three subject groups. Specific Aim 3: To correlate WBNAA and perfusion-MRI metrics against each other and with clinical measures of neurological and cognitive impairment, CSF and blood levels of TNF- and its soluble receptors. The health relatedness of this project: (i) To test quantitative MRI and 'H-MRS potential surrogate markers of disease activity that could facilitate effective monitoring of PP-MS in clinical trials, (ii) To investigate the relationship between microvascular changes, demyelination and neurodegeneration in MS. [unreadable] [unreadable]